The specific aims of this project are: (1) to search for the primary action and site of action of the diabetic alleles (db and db 2J) that cause a disease in mice resembling maturity-onset diabetes mellitus in man; (2) to define the physiology, biochemistry, and histopathology of the disease caused by these two alleles in different genetic backgrounds; and (3) to compare the effects of the diabetes alleles with those caused by unrelated alleles, in different genetic backgrounds; and (3) to compare the effects of the diabetes alleles with those caused by unrelated alleles, such as obese (ob) and the yellow alleles (Ay, Avy, and Aiy) which also cause hyperphagia, obesity, hyperinsulinemia, and mild hyperglycemia.